Eplepres film-coated tablets 25 mg blister No. 30

Instructions Eplepres film-coated tablets 25 mg blister No. 30

Composition

active ingredient: eplerenone;

1 tablet contains eplerenone 25 mg or 50 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; croscarmellose sodium; hypromellose (hydroxypropylmethylcellulose); sodium lauryl sulfate; talc; magnesium stearate;

shell: Opadry II Yellow 33G32799: hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; polyethylene glycol; triacetin; titanium dioxide (E 171); iron oxide yellow (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: round tablets with a biconvex surface, coated with a film coating from light brownish-yellow to light yellow.

Pharmacotherapeutic group

Potassium-sparing diuretics. Aldosterone antagonists. Eplerenone. ATC code C03D A04.

Pharmacological properties

Pharmacodynamics.

Eplerenone has a relative selectivity for binding to recombinant human mineralocorticoid receptors compared to its interaction with recombinant human glucocorticoid, progesterone, and androgen receptors. Eplerenone inhibits the binding of receptors to aldosterone, an important hormone of the renin-angiotensin-aldosterone system, which is involved in the regulation of blood pressure and is involved in the pathophysiological mechanisms of cardiovascular disease.

Eplerenone causes a sustained increase in plasma renin and serum aldosterone levels, which coincides with inhibition of the negative feedback pathway of aldosterone on renin secretion. However, increases in plasma renin activity and serum aldosterone levels do not lead to inhibition of eplerenone action.

In chronic heart failure (New York Heart Association (NYHA) class II–IV), the addition of eplerenone to standard treatment resulted in the expected dose-dependent increase in aldosterone levels.

It is known that in the cardio-nephrology substudy (study of the efficacy and mortality of eplerenone in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure), treatment with eplerenone resulted in a significant increase in aldosterone levels. The results obtained confirm the blockade of mineralocorticoid receptors in this population.

No consistent effect of eplerenone on heart rate, QRS complex duration, or PR and QT intervals was observed during the studies.

There have been reports of studies investigating the efficacy of eplerenone added to standard therapy on clinical outcomes in patients with mildly symptomatic systolic heart failure (NYHA functional class II).

Children: Eplerenone has not been studied in children with heart failure.

Studies of eplerenone at doses of 25-100 mg/day in children aged 4-16 years with hypertension have been reported. Effective blood pressure reduction was not achieved. Eplerenone has not been studied in children younger than 4 years with hypertension because studies in older children have shown a lack of efficacy (see section 4.2).

No studies have been conducted on any (long-term) effects on the hormonal status of children.

Pharmacokinetics.

Absorption: The absolute bioavailability of eplerenone following a 100 mg oral dose is 69%.

The maximum concentration of the drug in the blood plasma (Cmax) is reached after approximately 1.5-2 hours. Cmax and area under the pharmacokinetic curve (AUC) change proportionally to the dose in the range of 10-100 mg and less than dose-proportionally when using doses above 100 mg. The equilibrium state is reached within 2 days from the start of treatment. Food does not affect the absorption of the drug.

Distribution: Eplerenone is approximately 50% bound to plasma proteins and is primarily bound to α-1-acid glycoproteins. The apparent volume of distribution of eplerenone at steady state is estimated to be 42–90 L. Eplerenone does not bind to erythrocytes.

Biotransformation: Eplerenone is primarily metabolized by CYP3A4. No active metabolites of eplerenone have been identified in human plasma.

Elimination: Less than 5% of an eplerenone dose is excreted in the urine and feces as unchanged drug. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the feces and approximately 67% in the urine. The elimination half-life of eplerenone is approximately 3–6 hours. The apparent plasma clearance is approximately 10 L/h.

Age, gender, and race. Pharmacokinetics of eplerenone administered at a dose of 100 mg once daily have been studied in the following patient populations: elderly (≥65 years of age), male, female, and black patients. There were no significant differences in the pharmacokinetics of eplerenone between genders. Elderly patients had a 22% increase in Cmax and 45% in AUC at steady state compared with younger patients (18–45 years of age). In black patients, Cmax was 19% lower and AUC was 26% lower at steady state (see Dosage and Administration).

Children. Body weight was found to have a statistically significant effect on the volume of distribution of eplerenone, but not on its elimination. The volume of distribution of eplerenone and peak exposure in children with a higher body weight are expected to be similar to those observed in adults with a similar body weight. In patients weighing 45 kg, the volume of distribution is approximately 40% lower and peak exposure is expected to be higher than that typically observed in adults. Children were given an initial dose of 25 mg of eplerenone once daily; after 2 weeks, the dose was increased to 25 mg twice daily and, if clinically indicated, to 50 mg twice daily. At these doses, peak eplerenone concentrations in children were not significantly higher than those observed in adults given an initial dose of 50 mg once daily.

Renal impairment. The pharmacokinetics of eplerenone have been evaluated in patients with varying degrees of renal impairment and in patients undergoing hemodialysis. In patients with severe renal impairment, steady-state AUC and Cmax were increased by 38% and 24%, respectively, compared to controls. In patients undergoing hemodialysis, these values were decreased by 26% and 3%, respectively, compared to controls. There was no correlation between eplerenone plasma clearance and creatinine clearance. Eplerenone is not removed by hemodialysis (see section 4.4).

Hepatic impairment. The pharmacokinetics of eplerenone at a dose of 400 mg were studied in patients with moderate hepatic impairment (Child-Pugh B) and compared with those in patients without hepatic impairment. The steady-state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively (see section 4.2). Since eplerenone has not been studied in patients with severe hepatic impairment, eplerenone is contraindicated in such patients (see section 4.3).

Heart Failure: A pharmacokinetic study of eplerenone 50 mg in patients with heart failure (NYHA class II-IV) has been reported. Cmax and AUC at steady state in heart failure patients were 38% and 30% higher, respectively, than in age-, weight-, and sex-matched healthy volunteers. The clearance of eplerenone in heart failure patients is not different from that in healthy elderly volunteers.

Indication

Add-on to standard beta-blocker therapy to reduce the risk of cardiovascular morbidity and mortality in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure after a recent myocardial infarction.

Adjunct to standard optimal therapy to reduce the risk of cardiovascular morbidity and mortality in adult patients with NYHA class II (chronic) heart failure and left ventricular dysfunction (left ventricular ejection fraction ≤ 30%) (see section 5.1).

Contraindication

- Hypersensitivity to eplerenone or to any of the excipients of the drug.

- Patients with serum potassium levels > 5 mmol/L at the time of treatment initiation.

- Patients with severe renal insufficiency (estimated glomerular filtration rate < 30 ml/min/1.73 m2).

- Patients with severe hepatic impairment (Child-Pugh class C).

- Patients taking potassium-sparing diuretics or strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone) (see section “Interaction with other medicinal products and other forms of interaction”).

- Concomitant use of eplerenone in a triple combination with an ACE inhibitor and an angiotensin receptor blocker.

Interaction with other medicinal products and other types of interactions

Pharmacodynamic interactions.

Potassium-sparing diuretics and potassium supplements: Eplerenone should not be administered to patients receiving other potassium-sparing diuretics and potassium supplements due to the increased risk of hyperkalemia (see section 4.3).

ACE inhibitors, angiotensin receptor blockers. The risk of hyperkalemia may be increased when eplerenone is used in combination with an ACE inhibitor and/or angiotensin receptor blocker. Close monitoring of serum potassium and renal function is recommended, especially in patients at risk of renal impairment, such as the elderly. Eplerenone should not be used concomitantly in triple combination with an ACE inhibitor and an angiotensin receptor blocker (see sections 4.3 and 4.4).

Lithium: No interaction studies have been conducted with eplerenone and lithium. However, lithium toxicity has been reported in patients receiving lithium concomitantly with ACE inhibitors and diuretics (see section 4.4). The concomitant use of eplerenone and lithium should be avoided. If this combination cannot be avoided, plasma lithium levels should be monitored (see section 4.4).

Cyclosporine, tacrolimus. Cyclosporine and tacrolimus may cause renal dysfunction and increase the risk of hyperkalemia. The concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If cyclosporine and tacrolimus are necessary during treatment with eplerenone, careful monitoring of serum potassium is recommended (see section 4.4).

Nonsteroidal anti-inflammatory drugs (NSAIDs). Due to their direct effect on glomerular filtration, treatment with NSAIDs may lead to acute renal failure, especially in patients at high risk (elderly and/or dehydrated). Patients receiving eplerenone and NSAIDs should be adequately hydrated and their renal function monitored prior to initiation of treatment.

Trimethoprim. Concomitant use of trimethoprim and eplerenone increases the risk of hyperkalemia. Serum potassium and renal function should be monitored, especially in elderly patients and patients with impaired renal function.

α1-blockers (e.g. prazosin, alfuzosin). When combining α1-blockers and eplerenone, there is a possibility of increased hypotensive effect and/or development of orthostatic hypotension. During the simultaneous use of α1-blockers, the clinical condition of patients should be monitored for orthostatic hypotension.

Tricyclic antidepressants, neuroleptics, amifostine, baclofen. Concomitant use of these drugs and eplerenone may potentially potentiate the hypotensive effect and increase the risk of orthostatic hypotension.

Glucocorticoids, tetracosactide. When these drugs are used simultaneously with eplerenone, there is a possibility of weakening the hypotensive effect due to fluid and sodium retention.

Pharmacokinetic interactions.

In vitro studies indicate that eplerenone is not an inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6, or CYP3A4 isoenzymes. Eplerenone is not a substrate or inhibitor of P-glycoprotein.

Digoxin: Digoxin AUC increased by 16% (90% CI 4–30%) when co-administered with eplerenone. Caution should be exercised when administering digoxin at doses near the upper end of the therapeutic range.

Warfarin: No clinically significant pharmacokinetic interactions with warfarin have been described. Caution should be exercised when prescribing warfarin at doses near the upper end of the therapeutic range.

CYP3A4 Substrates: Pharmacokinetic studies with CYP3A4 substrate samples (i.e., midazolam and cisapride) did not reveal any evidence of significant pharmacokinetic interactions when these medicinal products were co-administered with eplerenone.

CYP3A4 inhibitors.

Potent CYP3A4 inhibitors. Concomitant use of eplerenone and medicinal products that inhibit the activity of the CYP3A4 enzyme may result in significant pharmacokinetic interactions. Under the influence of a potent CYP3A4 inhibitor (ketoconazole 200 mg twice daily), the AUC of eplerenone increased by 441% (see section 4.3). Concomitant use of eplerenone and potent CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone) is contraindicated (see section 4.3).

Weak and moderate CYP3A4 inhibitors: Co-administration with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole resulted in significant pharmacokinetic interactions with increases in AUC of 98-187%. Therefore, when eplerenone is co-administered with weak or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg/day (see Dosage and Administration).

CYP3A4 inducers. Concomitant use of eplerenone and St. John's wort (a strong CYP3A4 inducer) resulted in a 30% decrease in eplerenone AUC. Use of more potent CYP3A4 inducers (such as rifampicin) may result in a more pronounced decrease in eplerenone AUC. Due to the risk of decreased efficacy of eplerenone, concomitant use of potent CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) with this medicinal product is not recommended (see section 4.4).

Antacids: Based on the results of a clinical pharmacokinetic study, no significant interactions are expected with the concomitant use of eplerenone and antacid drugs.

Application features

Hyperkalemia. Due to its mechanism of action, hyperkalemia may occur during treatment with eplerenone. Serum potassium levels should be monitored in all patients at the start of treatment and during dose adjustments. Periodic monitoring is recommended thereafter, especially in patients at risk of hyperkalemia (such as the elderly, patients with renal impairment (see section 4.2) and diabetes). Potassium supplements are not recommended after initiation of eplerenone treatment due to the increased risk of hyperkalemia. Reducing the dose of eplerenone results in a decrease in serum potassium. In one study, the addition of hydrochlorothiazide to eplerenone compensated for the increase in serum potassium.

The risk of hyperkalemia may be increased when eplerenone is used in combination with an ACE inhibitor and/or an angiotensin receptor blocker.

Eplerenone should not be used concomitantly in a triple combination with an ACE inhibitor and an angiotensin receptor blocker (see sections 4.3 and 4.5).

Renal impairment. In patients with impaired renal function (including diabetic microalbuminuria), potassium levels should be monitored regularly. Decreased renal function is associated with an increased risk of hyperkalemia. An increased incidence of hyperkalemia has been observed in patients with type 2 diabetes and microalbuminuria. Accordingly, such patients should be treated with caution. Eplerenone is not removed by hemodialysis.

Hepatic impairment. In patients with mild to moderate hepatic impairment (Child-Pugh class A and B), serum potassium levels above 5.5 mmol/L were not observed. These patients require electrolyte monitoring. Eplerenone has not been studied in patients with severe renal impairment and is therefore contraindicated in these patients (see sections 4.2 and 4.3).

CYP3A4 inducers: Concomitant use of eplerenone and strong CYP3A4 inducers is not recommended (see section 4.5).

The use of lithium, cyclosporine, tacrolimus should be avoided during treatment with eplerenone (see section "Interaction with other medicinal products and other types of interactions").

Fertility: There is no information on the effect on human fertility.

The medicinal product contains lactose, therefore it should not be administered to patients with rare hereditary disorders (galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome).

Use during pregnancy or breastfeeding

Pregnancy: There are no adequate data from the use of eplerenone in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition, or postnatal development. Eplerenone should be administered with caution to pregnant women.

Breastfeeding. It is not known whether eplerenone is excreted in human milk after oral administration. However, nonclinical data indicate that eplerenone and/or its metabolites are present in the milk of rats and that the offspring exposed to eplerenone in this manner developed normally. Since the potential for adverse reactions in breastfed infants has not been studied, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect of eplerenone on the ability to drive or use machines have not been conducted. Eplerenone does not cause drowsiness or cognitive impairment, but when driving or operating machinery, the possibility of dizziness associated with the use of the drug should be taken into account.

Method of administration and doses

Adults.

Eplerenone can be administered with or without food (see Pharmacokinetics).

The maximum daily dose of the drug is 50 mg.

Patients with heart failure after myocardial infarction.

The recommended maintenance dose of eplerenone is 50 mg once daily. Treatment should be initiated at 25 mg once daily and titrated to a target dose of 50 mg once daily. This dose level should be achieved within 4 weeks, taking into account serum potassium levels (see table below).

Eplerenone treatment is usually initiated 3–14 days after acute myocardial infarction.

Treatment of patients with chronic heart failure class II according to the NYHA classification should be initiated at a dose of 25 mg once daily and gradually increased to a target dose of 50 mg once daily. It is advisable to reach this dose level within 4 weeks, taking into account the level of potassium in the blood serum (see table below and section "Special instructions").

Patients with serum potassium levels greater than 5 mmol/L should not initiate treatment with eplerenone (see section 4.3).

Serum potassium levels should be measured before initiating treatment with eplerenone, during the first week of treatment, and one month after initiation of treatment or dose adjustment. Serum potassium levels should be measured periodically during treatment as necessary.

After initiation of treatment, the dose of the medicinal product should be adjusted based on serum potassium concentration as indicated in the table below.

Dose adjustment after initiation of treatment

After temporary discontinuation of eplerenone due to an increase in potassium levels to ≥ 6 mmol/L, treatment can be resumed at a dose of 25 mg every 2 days after the potassium concentration decreases to below 5 mmol/L.

Elderly patients.

There is no need to adjust the initial dose of the drug for elderly patients. Due to age-related decline in renal function, the risk of developing hyperkalemia in elderly patients increases. The risk may be further increased in the presence of concomitant diseases that increase systemic exposure to the drug, including mild to moderate liver dysfunction. It is recommended to periodically monitor serum potassium levels (see section "Special warnings and precautions for use").

Kidney dysfunction.

Patients with mild renal impairment do not require adjustment of the initial dose. It is recommended to periodically monitor serum potassium levels (see section "Special warnings and precautions for use") and adjust the dose of the drug according to the table above.

Patients with moderate renal impairment (creatinine clearance 30-60 ml/min) should start treatment with 25 mg every other day and adjust the dose depending on the potassium concentration (see table above). Periodic monitoring of serum potassium is recommended (see section 4.4).

There is no experience in patients with creatinine clearance < 50 ml/min and heart failure after myocardial infarction. Eplerenone should be used with caution in these patients.

Doses greater than 25 mg/day have not been studied in patients with creatinine clearance < 50 mL/min.

Eplerenone is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.3). Eplerenone is not dialysable.

Liver dysfunction.

Patients with mild or moderate hepatic impairment do not require adjustment of the starting dose. Due to the increased systemic exposure to eplerenone, frequent and regular monitoring of serum potassium is recommended in these patients, especially in the elderly (see section 4.4).

Combined use.

In case of concomitant use with weak or moderate CYP3A4 inhibitors (e.g. amiodarone, diltiazem and verapamil), eplerenone treatment can be initiated at a starting dose of 25 mg once daily. The dose of the medicinal product should not exceed 25 mg once daily (see section 4.5).

Children

The safety and efficacy of eplerenone in children have not been established. Currently available information is provided in the Pharmacodynamics and Pharmacokinetics sections.

Overdose

Symptoms: There have been no reports of adverse reactions associated with eplerenone overdose in humans. The most likely manifestations of an overdose of the drug in humans would be hypotension or hyperkalemia.

Treatment. Eplerenone cannot be removed from the body by hemodialysis. Eplerenone is effectively bound to activated charcoal. In case of arterial hypotension, supportive treatment should be initiated. In case of hyperkalemia, treatment should be initiated according to standards.

Adverse reactions

Blood and lymphatic system disorders: eosinophilia.

From the endocrine system: hypothyroidism.

From the nervous system: dizziness, syncope, headache, hypesthesia.

Respiratory, thoracic and mediastinal disorders: cough.

Gastrointestinal: diarrhea, nausea, constipation, vomiting, bloating.

Skin and subcutaneous tissue disorders: rash, itching, hyperhidrosis, angioedema.

Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal pain, back pain.

Renal and urinary disorders: renal dysfunction (see sections “Interaction with other medicinal products and other types of interactions” and “Special instructions for use”).

Liver and biliary tract disorders: cholecystitis.

Reproductive system and breast disorders: gynecomastia.

From the psyche: insomnia.

Metabolism and digestion: hyperkalemia (see sections "Contraindications" and "Special instructions for use"); hyponatremia, dehydration, hypercholesterolemia, hypertriglyceridemia.

General disorders: asthenia, malaise.

Infections and infestations: infections, pyelonephritis, pharyngitis.

Laboratory tests: increased blood urea, increased creatinine, decreased epidermal growth factor receptors, increased blood glucose levels.

A study in patients ≥ 75 years of age reported a numerically higher incidence of stroke, but no statistically significant difference in stroke rates was found between the eplerenone (30) and placebo (22) groups.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after the marketing authorisation of a medicinal product is important. This allows for continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions in accordance with local requirements.

Expiration date

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

10 tablets in a blister; 3 blisters in a pack.

Vacation category

According to the recipe.

Producer

JSC "KYIV VITAMIN FACTORY".

Location of the manufacturer and address of its place of business

04073, Ukraine, Kyiv, Kopylivska St., 38.

Website: www.vitamin.com.ua